Elsevier

Progress in Neurobiology

Volume 65, Issue 5, December 2001, Pages 427-451
Progress in Neurobiology

Alterations induced by gestational stress in brain morphology and behaviour of the offspring

https://doi.org/10.1016/S0301-0082(01)00018-1Get rights and content

Abstract

Retrospective studies in humans suggest that chronic maternal stress during pregnancy, associated with raised plasma levels of CRH, ACTH and cortisol may increase the likelihood of preterm birth, developmental delays and behavioural abnormalities in the children. In adulthood, it may contribute to the significant association between the incidence of schizophrenia, increased left or mixed handedness, reduction in cerebral asymmetry and anomalies in brain morphology. Our studies and others have shown that prenatal stress in rats can mimic these developmental and behavioural alterations. These rats show a reduced propensity for social interaction, increased anxiety in intimidating or novel situations and a reduction in cerebral asymmetry and dopamine turnover, consistent with those in schizophrenic humans. Prenatally-stressed (PS) rats also show behaviour consistent with depression, including a phase-shift in their circadian rhythm for corticosterone, sleep abnormalities, a hedonic deficit and greater acquisition of learned helplessness under appropriate conditions. These behavioural abnormalities are associated with impaired regulation of the hypothalamic–pituitary–adrenal axis response to stress and increased CRH activity. PS males may show demasculinisation and feminisation of their sexual behaviour. The developmental and behavioural abnormalities in PS offspring could occur through sensitisation of the foetal brain by maternal stress hormones to the action of glucocorticoid and CRH and to neurotransmitters affected by them. This may have long-lasting consequences and could explain the precipitation of depressive symptoms or schizophrenia by psychosocial stress in later life. The character of the behavioural abnormalities probably depends on the timing of the maternal stress in relation to development of the particular neuronal systems.

Introduction

In recent years, there has been increasing awareness that various forms of pathological behaviour in humans may be the outcome of an interaction between genetic factors and the prenatal and postnatal environments. The early observations of Sontag (1941) of a relationship between adverse events creating an emotional disturbance in the pregnant mother and to feeding difficulties in the infants stimulated many studies on the possible effects of gestational stress on infant development and behaviour. Some authors reported an association between maternal psychological stress and birth weight, physical development (Jones and Tauscher, 1978, Knipschild et al., 1981, Lou et al., 1994), a higher incidence of emotional disturbance in their infants (Stott, 1973, Meijer, 1985, Ward, 1991) and hyperactivity-attention deficit disorder (Clements, 1992). An association was also described between maternal stress and an increased likelihood of Gilles de la Tourette's syndrome (TS) (Pasamanick and Kawi, 1956), schizophrenia and depressive symptomatology (Huttunen and Niskanen, 1978, Van Os and Selten, 1998, Watson et al., 1999) in prenatally stressed (PS) offspring. However, others failed to find any relationship between maternal stress and infant development or early or adult behaviour (Minde et al., 1968, Brooke et al., 1989, Selten et al., 1999). The inconsistencies in the earlier studies and difficulties in their interpretation may stem from methodological weaknesses. These include failure to account for genetic factors, parity, concomitant illness, smoking, alcohol or drug intake, timing of stress exposure and whether the stress was a single episode or recurrent. There may also be bias in retrospective reporting of gestational events by mothers of children with behavioural abnormalities. Furthermore, little attention has been devoted to defining psychological stress, to developing appropriate ways to measure it, or to account for individual differences in coping with it. The methodological shortcomings of these earlier studies are described in detail in a review by Lobel (1994).

Low birth weight and preterm delivery are major determinants of infant morbidity (Newton and Hunt, 1984, McCormick, 1985, Verloove-Vanhorick et al., 1986, Hakulinen et al., 1988). The latter includes neurological and behavioural aberrations in the surviving infants (Taylor et al., 1985, Holst et al., 1989, Hadders-Algra et al., 1988). More carefully controlled prospective and retrospective studies have been able to show that adverse life events during pregnancy and/or self-reported anxiety are indeed associated with low birth weight (less than 2.5 kg) and/or preterm delivery (before the 37th week) (Mutale et al., 1991, Steer et al., 1992, Hedegaard et al., 1993, Hedegaard et al., 1996, Wadhwa et al., 1993, Zambrana et al., 1999). However, while birth weight and length of gestation can reasonably be related to maternal stress, after other confounding factors have been controlled, such a relationship is much more difficult to show for neurological and behavioural pathology in the offspring for several reasons. First, there may be a strong genetic component in the mediation of these behavioural aberrations (O'Connor et al., 1998, Bierut et al., 1999, Tsuang, 2000). Second, the environmental or social circumstances that engendered the stress in the mother may continue after the birth of the infant and affect its development and behaviour either directly or through rearing by an overanxious mother. Third, abnormal behaviour in infants, children or adults may not be so readily detected under control conditions but only during a mildly stressful event, such as exposure to the novel environment of a school or kindergarten (Meijer, 1985). This was shown to occur in experimental animals (see Sections 5.3 and 5.4). Lastly, pathological behaviour like schizophrenia or depression only becomes manifest some decades after gestation necessitating the acquisition of information about gestational events from medical records, which may be incomplete, or from maternal recollection, which may be influenced by her knowledge of behavioural abnormalities in her child. Environmental and genetic factors are more easily controlled in studies on the effect of gestational stress in experimental animals. However, the range of behavioural abnormalities is much more limited and cannot always be related to those in human subjects. The aim of this review is to evaluate critically the evidence from human and animal studies for a role of prenatal stress in the aetiology of behavioural pathology.

Section snippets

Methods of assessment

Research on the effects of psychological stress or adverse life events during pregnancy on the development and behaviour of the offspring can broadly be classified into two groups. The first are those in which the mother was not interviewed, but it was presumed that she was under severe psychological stress because she experienced adverse life events or more serious emotional trauma. These include natural disasters, such as floods (Selten et al., 1999) or earthquakes (Watson et al., 1999), or

Comparative brain development in foetal rats and humans

The majority of experiments on the effects of gestational stress on development and behaviour in the offspring have been carried out in rats, because sufficient numbers can be included in each study to obtain statistically significant differences between experimental and control groups. There are also a few studies in Rhesus and squirrel monkeys that largely support the direction of the findings in rats. (Schneider, 1992, Clarke and Schneider, 1993). Any attempt to extrapolate from data on the

Effect of gestational stress on the hypothalamic–pituitary–adrenal axis

Activation of the HPA axis in response to psychological stress in the pregnant female could play an important role in the regulation of the stress response in the offspring in later life and may be responsible for some of their behavioural pathology.

Methodological considerations

Studies on the effects of gestational stress in experimental animals have the advantage that one can more easily control for potential genetic differences, the timing and intensity of the stress, and the postnatal environment than in human subjects. However, they still do not enable us to assess accurately the degree of fear or anxiety engendered by the stress in the mother and her physiological and emotional response to it. This also has a genetic component since it varies considerably in

Conclusions

The data from human subjects and experimental animals suggest that chronic gestational stress can have long-term effects on neuronal development. This may induce different types of behavioural pathology that can be detected in infancy and persist into adulthood. The nature of the behavioural abnormalities are probably determined by the time of occurrence of the maternal stress in relation to the stage of development of particular neuronal systems. The putative mechanisms involve an interaction

References (257)

  • R.J. Davidson et al.

    The functional neuroanatomy of emotion and affective style

    Trends Cogn. Sci.

    (1999)
  • E.R. De Kloet et al.

    Stress, glucocorticoids and development

    Prog. Brain Res.

    (1988)
  • M.C. Diamond et al.

    A comparison of cortical thickness in male and female rats: normal and gonadectomized, young and adult

    Behav. Neural Biol.

    (1979)
  • F. Drago et al.

    Prenatal stress induces body weight deficit and behavioural alterations in rats: the effect of diazepam

    Eur. Neuropsychopharmacol.

    (1999)
  • A.J. Dunn et al.

    Physiological and behavioral responses to corticotrophin-releasing factor administration: is CRF a mediator of anxiety or stress responses?

    Brain Res. Rev.

    (1990)
  • A.J. Dunn et al.

    Corticotropin-releasing factor has an anxiogenic action in the social interaction test

    Horm. Behav.

    (1987)
  • S.E. File

    The rat corticosterone response: habituation and modification by chlordiazepoxide

    Physiol. Behav.

    (1982)
  • D.E. Fleming et al.

    Effect of prenatal stress on sexually dimorphic asymmetries in the cerebral cortex of the male rat

    Brain Res. Bull.

    (1986)
  • A. Foerster et al.

    Low birth weight and a family history of schizophrenia predict pre-morbid functioning in psychosis

    Schizophr. Res.

    (1991)
  • E. Fride et al.

    Prenatal stress impairs maternal behavior in a conflict situation and reduces hippocampal benzodiazepine receptors

    Life Sci.

    (1985)
  • E. Fride et al.

    Effects of prenatal stress on vulnerability to stress in prepubertal and adult rats

    Physiol. Behav.

    (1986)
  • E. Fride et al.

    Prenatal stress increases anxiety-related behavior and alters cerebral lateralization of dopaminergic activity

    Life Sci.

    (1988)
  • E. Fride et al.

    Alterations in behavioral and striatal dopamine asymmetries induced by prenatal stress

    Pharmacol. Biochem. Behav.

    (1989)
  • T. Fujioka et al.

    The effects of prenatal stress on the development of hypothalamic paraventricular neurons in fetal rats

    Neuroscience

    (1999)
  • H.J. Ginsburg et al.

    Inhibition of distress vocalizations in the open field as a function of heightened fear or arousal in the domestic fowl (Gallus gallus)

    Anim. Behav.

    (1974)
  • S.D. Glick et al.

    Lateral asymmetry of neurotransmitters in human brain

    Brain Res.

    (1982)
  • R.J. Handa et al.

    Gonadal steroid hormone receptors and sex differences in the hypothalamo–pituitary–adrenal axis

    Horm. Behav.

    (1994)
  • A. Hayashi et al.

    Maternal stress induces synaptic loss and developmental disabilities of offspring maternal stress

    Int. J. Dev. Neurosci.

    (1998)
  • C. Henry et al.

    Prenatal stress in rats facilitates amphetamine-induced sensitization and induces long-lasting changes in dopamine receptors in the n. acc

    Brain Res.

    (1995)
  • R.H.M. Hermans et al.

    Altered adult sexual behavior in the male rat following chronic prenatal hypoxia

    Neurotoxicol. Teratol.

    (1993)
  • R.R. Holson et al.

    Prenatal dexamethasone or stress but not ACTH or corticosterone alter sexual behavior in male rats

    Neurotoxicol. Teratol.

    (1995)
  • E.J. Houtsmuller et al.

    SDN-POA volume, sexual behavior, and partner preference of male rats affected by perinatal treatment with ATD

    Physiol. Behav.

    (1994)
  • P. Jones et al.

    Child development risk factors for adult schizophrenia in the British 1946 birth cohort

    Lancet

    (1994)
  • E.D. Abercrombie et al.

    Differential effect of stress in in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex

    J. Neurochem.

    (1989)
  • S.F. Akana et al.

    Feedback and facilitation in the adrenocortical system: unmasking facilitation by partial inhibition of the glucocorticoid response to prior stress

    Endocrinology

    (1992)
  • S.W. Anderson et al.

    Impairment of social and moral behavior related to early damage in human prefrontal cortex

    Nat. Neurosci.

    (1999)
  • L. Arborelius et al.

    The role of corticotropin-releasing factor in depression and anxiety disorders

    J. Endocrinol.

    (1999)
  • J. Archer et al.

    Prenatal psychological stress and offspring behavior in rats and mice

    Dev. Psychobiol.

    (1971)
  • D.G. Armaral et al.

    Anatomical organization of the primate amygdaloid complex

  • J.M. Bailey et al.

    A test of the maternal stress theory of human male homosexuality

    Arch. Sex. Behav.

    (1991)
  • A. Barbazanges et al.

    Maternal glucocorticoid secretion mediates long-term effects of prenatal stress

    J. Neurosci.

    (1996)
  • S.A. Bayer et al.

    Timetables of neurogenesis in the human brain based on experimentally determined patterns in the rat

    Neurotoxicology

    (1993)
  • H. Beckmann et al.

    Prenatal disturbances of nerve cell migration in the entorhinal region: a common vulnerability factor in functional psychoses?

    J. Neural Transm.

    (1991)
  • A. Bertolini et al.

    Regionally specific neuronal pathology in untreated patients with schizophrenia: a proton magnetic resonance spectroscopic imaging study

    Biol. Psychiatry

    (1998)
  • L.J. Bierut et al.

    Major depressive disorder in a community-based twin sample: are there different genetic and environmental contributions for men and women?

    Arch. Gen. Psychiatry

    (1999)
  • F. Boudouresque et al.

    Maturation of the pituitary–adrenal function in rat fetuses

    Neuroendocrinology

    (1988)
  • H.S. Bracha et al.

    Second-trimester markers of fetal size in schizophrenia: a study of monozygotic twins

    Am. J. Psychiatry

    (1992)
  • D. Braff et al.

    Prestimulus effects on human startle reflex in normals and schizophrenics

    Psychophysiology

    (1978)
  • O.G. Brooke et al.

    Effects on birth weight of smoking, alcohol, caffeine, socioeconomic factors, and psychosocial stress

    Br. Med. J.

    (1989)
  • A.S. Brown et al.

    Further evidence of relation between prenatal famine and major affective disorder

    Am J. Psychiatry

    (2000)
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    Leon & Mina Deutsch Professor of Psychopharmacology.

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